TY  - CHAP
M1  - Book, Section
TI  - Rett Syndrome
A1  - Zoghbi, Huda Y.
A1  - Francke, Uta
A2  - Valle, David L.
A2  - Antonarakis, Stylianos
A2  - Ballabio, Andrea
A2  - Beaudet, Arthur L.
A2  - Mitchell, Grant A.
Y1  - 2019
N1  - 10.1036/ommbid.426
T2  - The Online Metabolic and Molecular Bases of Inherited Disease
AB  - Rett  syndrome  (RTT)  is  an  X-linked  dominant  neurodevelopmental  disorder  that  afflicts  females  after  6  to  18  months  of  apparently  normal  development.  Around  this  time,  they  enter  a  short  period  of  developmental  stagnation  followed  by  rapid  regression  in  language  and  motor  development.  A  hallmark  of  RTT  is  the  loss  of  purposeful  hand  use  followed  by  repetitive,  stereotyped  hand  movements.  Additional  features  include  autistic  behavior,  gait  ataxia  and  apraxia,  seizures,  episodic  apnea  and/or  hyperpnea,  bruxism,  and  acquired  microcephaly.  After  this  period  of  rapid  deterioration,  the  disease  becomes  relatively  stable,  but  patients  reaching  the  second  or  third  decade  may  show  additional  neurologic  abnormalities,  such  as  seizures,  dystonia,  parkinsonism,  spasticity,  and  kyphoscoliosis.  X-linked  inheritance  explains  the  existence  of  a  few  males  with  severe  neonatal  encephalopathy  born  into  families  affected  by  RTT.No  laboratory  findings  have  proven  consistent  enough  to  be  diagnostically  useful.  The  EEG  is  typically  normal  for  the  first  2  years  of  life,  after  which  patients  lose  occipital  dominant  rhythm  and  background  activity.  CT  and  MRI  show  cortical  atrophy  and  sometimes  narrowing  of  the  brain  stem;  PET  reveals  reduced  cerebral  blood  flow  in  the  prefrontal  and  temporoparietal  association  regions.  Brains  of  RTT  patients  weigh  less  than  age-matched  controls;  there  is  mild  cortical  and  cerebellar  atrophy  but  no  evidence  of  neuronal  loss.  Select  neuronal  populations  show  reduced  dendritic  arborization,  smaller  neuronal  size,  and  increased  neuronal  density.Current  effective  management  of  RTT  patients  focuses  on  supportive  and  symptomatic  therapy,  for  example,  anticonvulsants  for  seizures,  chloral  hydrate  for  agitation,  carbidopa/levodopa  for  rigidity,  and  melatonin  for  sleep  disturbances.  Nutritional  management  is  important  to  ensure  adequate  caloric  and  fiber  intake.RTT  is  caused  by  any  of  various  mutations  in  the  the  gene  that  encodes  methyl  CpG-binding  protein  2  (MECP2)  gene,  which  encodes  the  methyl  CpG-binding  protein  2.  This  ubiquitous  protein  assists  in  transcriptional  silencing  by  binding  to  symmetrically  methylated  single  CpGs  in  double-stranded  DNA.  The  transcriptional  repression  domain  binds  to  the  corepressor  Sin3A  and  recruits  histone  deacetylases  and  other  proteins  to  the  silencing  complex.  When  lysine  residues  of  the  core  histones  H3  and  H4  become  deacetylated,  the  chromatin  structure  changes  and  renders  the  DNA  inaccessible  to  the  transcriptional  machinery.  The  heritability  of  the  repressed  state  depends  on  maintenance  of  CpG  methylation  through  replication  by  the  maintenance  methylase  that  acts  on  hemimethylated  DNA.The  severity  of  the  RTT  phenotype  is  determined  primarily  by  the  female's  pattern  of  X  inactivation  (XCI),  but  the  type  of  mutation  could  also  have  an  influence.  Individuals  who  meet  the  diagnostic  criteria  for  RTT  have  more  or  less  random  XCI.  Rare  cases  with  skewed  XCI  might  be  severely  affected  and  lack  a  period  of  normal  early  development  if  the  mutant  X  is  predominantly  active.  Patients  with  the  normal  X  predominantly  active  have  milder  presentation.  Extreme  skewing  can  cause  nonspecific  learning  deficits  in  women  for  whom  a  diagnosis  of  RTT  would  not  have  been  considered;  so  far,  such  women  have  been  identified  only  because  of  relation  to  individuals  with  classic  RTT.  Indications  for  mutation  testing  extend  beyond  individuals  with  the  clinical  diagnosis  of  RTT  to  include  females  with  partial  phenotypes  who  do  ...
SN  - 
PB  - McGraw-Hill Education
CY  - New York, NY
M3  - doi: 10.1036/ommbid.426
Y2  - 2024/04/16
UR  - ommbid.mhmedical.com/content.aspx?aid=1184073216
ER  -